Preventing osteoporotic bone loss in mice by promoting balanced bone remodeling through M-CSF, a dual antagonist to c-FMS and αvβ3 receptors.

Osteoporosis is a common, age-related disease caused by imbalanced bone remodeling. Current treatments either shut down bone resorption or robustly stimulate bone formation. Here, we describe a novel compound that inhibits osteoclast activity without causing apparent disruptions to bone formation by targeting both c-FMS (i.e., osteoclast differentiation) and αvβ3 integrin (i.e., osteoclastic bone resorption) receptors. We show that human serum albumin (HSA)-conjugated M-CSF protein (M-CSF-HSA) effectively inhibits the activity of both receptors, with a three-fold higher serum half-life compared to the unconjugated M-CSF. We then treated ovariectomized mice with different doses of M-CSF-HSA, alendronate, or a monospecific control protein. The bispecific M-CSF-HSA was superior to a monospecific control in alleviating bone loss and reducing osteoclast distribution and function. M-CSF-HSA and alendronate effectively prevented ovariectomy-induced bone loss, but M-CSF-HSA had a milder inhibitory effect on osteoclast distribution and activity. Moreover, alendronate halted bone formation, while M-CSF-HSA-treated mice showed an increased level of serum amino-terminal propeptide of type I collagen, a bone formation marker. Our data indicate that the mild reduction in osteoclast activity facilitated by the bispecific M-CSF-HSA allows the maintenance of certain levels of bone formation and may be superior to treatments that induce osteoclast depletion.